The invention relates to medicine and, more specifically, to a novel pharmaceutical composition useful in the treatment of ischemic heart disease and capable of limiting the necrotic zone in myocardial infarction.
The ischemic heart disease and myocardial infarction are the most widespread diseases that affect humans. They are a leading cause of high mortality among patients, which dictates the need for a further search of novel therapeutic drugs.
It is well known that myocardial infarction is associated with lipid peroxidation and, due to an insufficient oxygen supply, is often accompanied by the formation of an extensive necrotic zone in the heart.
Various cardioprotective agents based on antioxidants are known in the art (RU 2 070 027; WO 97/38681). Emoxipin is one of such agents known for its ability to protect the myocardium against the reperfusion damage.
Emoxipin was intravenously administered in a dose of 10 mg/kg to a group of 26 patients before a thrombolytic reperfusion. In the control group no protective agent was administered prior to the thrombolytic reperfusion. Pretreatment with the protective agent (Emoxipin) resulted in a reduction of the size of the asynergic zone in the myocardium (by 59.5% versus 39.2% in the control group), in a significant decrease in the frequency of myocardial arrhythmias (13.9% versus 28.1%), as well as significantly decreasing, as compared with monotherapy, lipid peroxidation in terms of malonic dialdehyde concentration (60% versus 309%) (cf. Maksimov I. V. et al. Protection against reperfusion damage in thrombolysis cases in patients with acute myocardial infarction. Proceedings of the IVth Russian National Conference xe2x80x9cPeople and Drugsxe2x80x9d, Apr. 8-12, 1997, Moscow, p. 274).
The objective of the present invention is to provide a novel and highly effective pharma-ceutical composition with antiischemic and antiinfarction effects, which would also meet the requirements that apply to injectable formulations.
The pharmaceutical composition of the present invention has been specifically developed for the treatment of acute myocardial infarction and ischemic heart disease in the form of an aqeous solution for injection, comprising di- and trisodium salts of echinochrome. The novel compounds are prepared by reacting echinochrome with sodium carbonate. The inventors established appropriate conditions under which a chemical interaction between the salt of a weak acid (sodium carbonate) and an organic compound (echinochrome) produces water-soluble sodium derivatives of echinochrome, in which 2 to 3 sodium ions are present per molecule of echinochrome.
Echinochrome, or 2,3,5,6,8-pentahydroxy-7-ethyl-1,4-naphthoquinone, is produced from a natural source (sea urchins, Latin echini), or by chemical synthesis.
The novel pharmaceutical composition Histochrome (trade mark) represents an isotonic solution for injections, containing a mixture of di- and trisodium salts of echinochrome in an amount of 0.90 to 1.10 g/ml. The solution is sterilized by filtration through membrane filters and poured anaerobically into 5 ml or 10 ml ampoules made of neutral glass. The ready-to-use composition is packaged in batches of 5-10 ampoules into boxes lined with PVC and aluminum foil. The boxes are placed into packs and 10-60 packs are placed into cardboard boxes and labeled in accordance with the requirements. The composition is stored protected from light at a room temperature not exceeding 25xc2x0 C. It has a shelf life of 3 years.
The composition is an opaque liquid, brownish black in color.
The content of echinochrome, which is formed when Histochrome is acidified with hydrochloric acid, is determined spectrophotometrically. The optical density of a sample of the composition in acidified alcohol is compared with the optical density of a standard solution with a known concentration of echinochrome prepared under identical conditions.
The active ingredient is identified by its spectrum in acidified ethanol, which in the range of 250 to 600 nm has two absorption maxima (342xc2x12 nm and 468xc2x12 nm) and two absorption minima (295xc2x12 nm and 394xc2x12 nm).
The presence of sodium ions in the composition is qualitatively verified by a yellow colour of the burning flames.
The pH of the composition is 7.2 to 8.0.
The composition is apyrogenic to animals at a dose of 5 mg/kg body weight and is non-toxic at a test-dose of 1 mg per mouse.
The composition is sterile.
Clinical studies of Histochrome confirmed its high efficiency in the treatment of ischemia and acute myocardial infarction, namely:
histochrome reduces the zone of necrosis by 57% in patients with acute myocardial infarction;
it restores the contractility of the left ventricle, reduces the frequency of reperfusion-induced ventricular arrhythmias, and produces an antiarrhythmogenic effect in patients with acute myocardial infarction;
it suppresses the aggregation of erythrocytes and thrombocytes and produces a desaggregative effect in cases of acute myocardial infarction;
it has a beneficial effect upon the clinical course of the heart disease, reduces the incidence of complications and lethal outcomes in patients with acute myocardial infarction, and it is well tolerated by patients.